2{40 ,3{40 -o-lower alkylidene or cyclohexylidene periplorhamnoside compounds

ABSTRACT

Periplorhamnoside derivatives of the general formula   WHEREIN R1 may be hydrogen, methyl, ethyl, methoxymethyl, ethoxymethyl or the acyl residue of a carboxylic acid having 1 to 5 carbon atoms, R2 and R3 may be equal or different, each, representing a lower alkyl or, together with the common carbon atom, form a 5 or 6 membered alicyclic ring. The compounds of the present invention possess cardiotonic activity.

United States Patent [191 Hartenstein et al.

1 Dec. 3, 1974 1 2',3'-O-LOWER ALKYLIDENE OR CYCLOHEXYLIDENEPERIPLORHAMNOSIDE COMPOUNDS [75] Inventors: Johannes HermannHartenstein,

Wittental', Gerhard Satzinger, 1m. Mattenbuhl, both of Germany [73]Assignee: Warner-Lambert Company, Morris Plains, NJ.

[22] Filed: Oct. 5, 1972 [21] Appl. No.: 295,384

[52] US. Cl. 260/2105, 424/182 Primary Examiner-Johnnie R. BrownAssistant ExaminerCary Owens Attorney, Agent, or FirmAlbert 1-1.Graddis; Frank S. Chow [57] ABSTRACT Periplorhamnoside derivatives ofthe general formula wherein R, may be hydrogen, methyl, ethyl,methoxymethyl, ethoxymethyl or the acyl residue of a carboxylic acidhaving 1 to 5 carbon atoms, R and R may be equal or different, each,representing a lower alkyl or, together with the common carbon atom,form a 5 or 6 membered alicyclic ring. The compounds of the presentinvention possess cardiotonic activity.

6 Claims, No Drawings Periplorham'noside derivatives of the generalformulaona wherein R may be hydrogen, methyl, ethyl, methoxymethyl,ethoxymethyl or the acyl residue of a carboxylic acid having 1 to 5carbon atoms, R and R may be equal or different, each representing alower alkyls or, together with the common carbon atom, form a 5 or 6membered alicyclic ring. These derivatives permit oral administration ofcompounds which have a cardiotonic effect.

Periplorhamnoside, the a-L-rhamnoside of the periplogenin, is found inthe seeds of Antiaris toxicaria, Lesch (Reichstein et al., Helv. 47,2164 (i964) and in the flowers and leaves of Convallaria majalis L.(Kubelka et al., Monatsh. Chem, 48, 1262 (1967) and can also be obtainedby means of partial synthesis from convallatoxin (Reichstein et al.,Helv. 46, 117 (1963) or periplogenin. Due'to the structure of itsaglycon (methyl group linked to C-lO) the periplorhamnoside isinteresting for its position intermediate between the cardiac glycosidesof the digitalis type and of the strophanthus type. It surpassesconvallatoxin in its biological action but is, like the latter, absorbedonly to a small extent upon enteral administration.

Most surprisingly it has now been found that the compounds according tothe invention show a good enteric effectiveness, to some exte t they areeven more effective in enteral than in parenteral application whichmeans that for the first time the periplorhamnoside can be utilized fororal therapy of a cardiac insufficiency.

The compounds according to the invention are prepared by reacting theperiplorhamnoside with a ketone in the Presence of a dehydrating agentand an acid acting as catalyst at room temperature or at moderatelyincreased temperature and, if desired, by alkylating or acylating underusual conditions the compound thus obtained.

The reaction may take place in an inert solvent such as dioxane,tetrahydrofuran, or preferably in an excess of the carbonyl compound tobe reacted.

The usual dehydrating reagents are suited for effecting theketalization; anhydrous copper sulfate is preferred. For obtaining agood yield it proved advantageous to carry out the reaction, in thepresence of an acid, preferably p-tluene-sulfonic-acid-monohydrate.

Thus the reaction takes place rapidly and the formation of by-productsis almost completely suppressed.

Another variant of the process for preparing the ketal derivatives isthe transketalization of suitable dialkylketals by periplorhamnoside inthe presence of catalytic amounts of an acid such as p-toluene-sulfonicacid-monohydrate.

The alkylation ofthe ketal derivatives is affected by a reaction withsuitable alkylation agents as, e. g., dialkylsulfates or alkylhalides inthe presence of an acid acceptor at room temperature or at moderatelyincreased temperature.

The acylation is affected, according to known methods, with reactiveacid derivatives as, e.g., acid halides, acid anhydrides, or mixedanhydrides in an inert solvent in the presence of an acid binding agentat tempera s sssf (-2.5 t is fur he a xamase to Sean excess of pyridinewhich also serves as solvent.

' After work-up in the usual way the products of the process areisolated either by meansv of chromatographic purification on silica gelor directly by crystallization. I i

The compoundsaccording to the invention exert a positive-inotropiceffect on the heart muscle of various kinds of mammals. They may be usedin forms suitable for oral administration or as injection preparationsfor the treatment of cardiac or circulatory diseases. For this purposethey are processed with carriers and adjuvant substances customary ingalenic pharmaceutics and then formed in principally known manner intothe desired administration form. Qualified forms are tab lets, coatedtablets, capsules, suppositories, drops and ampuls. Quantity andfrequency of dosage depend on the degree of severity of the case to betreated, with 0.1

to. 1.0 mg of active ingredient being recommended as the usual dose.

The following examples serve to illustrate the method for preparing thenew compounds according to the invention.

EXAMPLE 1 2,3-O-isopropylidene-periplorhamnoside 300 Mg ofperiplorhamnoside are dissolved in 10 ml of distilled acetone andstirred with l g of anhydrous copper sulfate and 50 mg ofp-toluene-s'ulfonic acid monohydrate for 3.5 hrs. at room temperature.Subsequently the mixture is filtered, and after addition of 5 sodiumbicarbonate solution, concentrated under reduced pressure. Subsequentlythe product is extracted with chloroform, the extract washed with water,and following drying and concentration under reduced pressure acolorless foam is obtained which is chr0- matographed on silica gel(Merck 0.05 0.2 mm). Elution with chloroform/methanol 98:2 (v/v) affords216 mg of product. By reprecipitation from chloroform with petroleumether 2',3-O-isopropylidene-periplor hamnoside is obtained as white,amorphous powder, mp. l45-l48C.

1381, 1075, 104i crn' NMR-spectrum (CDC13, a in ppm): 0,89(s,3H),

EXAMPLE 2 2,3'-O-cyclohexylidene-periplorhamnoside 300 Mg ofperiplorhamnoside are dissolved in 15 ml of cyclohexanone, mixed with 2g of anhydrous copper sulfate and 50 mg of'p-toluene-sulfonic acidmonohydrate. The mixture is stirred at room temperature for 10 Cale: c67.17 H 8.52 24.29 Found: 67.38 8.35

lR-spectrum (KBr): inter alia 1779/1742, 1621, 1041 NMR-spectrum(CDCl;,), 8 in ppm): 0,90(s,3H), 0,95(s,31-1), -1,27(d,3H),4,92(m,2l-1), 5,l4(s,lH), 5,90(m,1H) I EXAMPLE 34'-O-acetyl-2,3-O-isopropy1idene-periplorhamnoside 150 Mg ofisopropylidene-periplorhamnoside (cf. example l) are dissolved in 5 mlof pyridine and mixed withS ml of acetic anhydride. The mixture isallowed to stand overnight at room temperature and is subsequentlypoured into 50 ml of ice water, and extracted with chloroform. Usualwork-up and crystallizing from methanol/water affords 106 mg ofcrystalline product, m.p. 23337C.

C23H50O10 Calc.:-' c 65.99 H 8.15 0 25.86 Found: 65.85 7.84: 26.05

lR-spectrum (KBr): inter alia 1761/1718, 1618,

EXAMPLE 4 4'-O-acetyl-2',3'-O?cyclohexylidene-periplorhamnoside 400 mgof cyclohexylidene-periplorhamnoside (cf. example 2) are dissolved in 5ml of pyridine and mixed with 5 ml of acetic anhydride. The mixture isallowed to stand at room temperature for 12 hrs. is subsequently pouredinto ice water and the product is extracted with chloroform. Usualwork-up and chromatography of the crude product on silica gel (Merck,

0.05 0.2 mm; eluent: chloroform) and reprecipitation afford 378 mg ofproduct as white, amorphous powder, m.p. 1343 5C.

CSIHMOIO Cale; Found:

tow

lR-spectrum (KBr): inter alia 1764/1724, 1610,

I362, 1222, 1036 (:n'F NMR-spectrum (CDCIQ) 3 in ppm)- EXAMPLE 54'-%-acetyl-2,3-O-sec.butylidene-periplorhamnosi e 300 Mg ofperiplorhamnoside are dissolved in 10 ml of methylethylketone and mixedwith 2 ml of 2,2- dimethoxybutane and 25 mg of p-toluene-sulfonic acidmonohydrate. The mixture is stirred for 1 hour at room temperature,neutralized with 5 aqueous sodium bicarbonate solution, concentratedunder reduced pressure and extracted with chloroform. After drying andconcentration the ketal formed is dissolved in 5 ml of pyridine andmixed with 5 ml of acetic anhydride. The

product is allowed to stand overnight and processed as described inexample 3. After chromatography on silica gel and reprecipitation fromchloroform/petroleum ether 184 mg of product are obtained as amorphous,white powder, m.p. 12629C.

C35H52O10 cam; c 6643 H 8.28 0 25.29 Found: 66.50 7.97 25.27

IR-spectrum (KBr): inter alia 1767/1730, 1613,

NMR-spectrum (CDCl 8 in ppm): 0,89(s,3H), 0,95(s,31-1), 1,16(d,31-1),2,10 (s,3H), 4,84(m,1H), 4,90(m,2H), 5,1l(s,lH), 5,86(m ,1H)

What is claimed is:

l. Periplorhamnoside derivatives of the formula:

. CH3 1 V R10 OH .-P a V o o wherein R is selected from the groupconsisting of hydrogen, methyl, ethyl, methoxy-methyl, ethoxy-methyl,and the acyl residue of a carboxylic acid with 1 to 5 carbon atoms; andwherein R and R taken individually are lower alkyls, or taken togetheris a 5 or 6 membered alicyclic rin 2. Wherem the derivatives of claim 1is 2',3'-O- isoprop lideneperiplorhamnoside.

3. W erein the derivatives of claim 1 is 2',3'-O- cyclohexylideneperiplorhamnoside.

4. Wherein the derivatives of claim I is 4'-O-acetyl-2',3'-()-isopropylidene-periplorhamnoside.

5. Wherein the derivatives of claim 1 is 4'-O-acetyl-2',3'-O-cyclohexylidene-periplorhamoside.

6. wherein the derivatives of claim 1 is 4'-O-acetyl- 2',3-osec.butylidene-periplorhamnoside.

1. PERIPLORHAMNOSIDE DERIVATIVES OF THE FORMULA:
 2. Wherein thederivatives of claim 1 is 2'',3''-O-isopropylideneperiplorhamnoside. 3.Wherein the derivatives of claim 1 is 2'',3''-O-cyclohexylideneperiplorhamnoside.
 4. Wherein the derivatives of claim 1 is4''-O-acetyl-2'',3''-O-isopropylidene-periplorhamnoside.
 5. Wherein thederivatives of claim 1 is4''-O-acetyl-2'',3''-O-cyclohexylidene-periplorhamoside.
 6. Wherein thederivatives of claim 1 is 4''-O-acetyl-2'',3''-o-sec.butylidene-periplorhamnoside.